Saturday, August 31, 2013

ADAPTER PROTEINS: A CLASS OF "WILD GENES"

We have venture to define "wild genes" as class of genes that have multiple interactions leading to uncontrolled neoplastic processes.   A particular note has to be noted about Adapter proteins (ie.Gerb2)
The notion that their standard description suggests they do not have intrinsic enzymatic properties tend to minimize their actual role.  Indeed these genes act as "obligatory cofactors" in many cancers.  Kantarjian et al discussing Chronic Myeloid leukemia reported: "Many of these interactions are mediated through tyrosine phosphorylation and require binding of the BCR-ABL to adapter proteins such as the Grb2, CRK, CRK like proteins(CRKL), and SCR-homology containing proteins (SHC)".  In fact, downstream events will not effectively happen without these "enablers", making them an equal partner in crime.
Now going after these Adapters may prove dicey as it is assumed that they are also extensively found in normal tissue but who really knows until all phases of trials are completed.
Wikipedia:
"Signal transducing adaptor proteins are proteins which are accessory to main proteins in a signal transduction pathway. Adaptor proteins contain a variety of protein-binding modules that link protein-binding partners together and facilitate the creation of larger signaling complexes. These proteins tend to lack any intrinsic enzymatic activity themselves[1] but instead mediate specific protein–protein interactions that drive the formation of protein complexes. Examples of adaptor proteins include MyD88, Grb2 and SHC1."

and the list goes on:


Genes encoding adaptor proteins include:
  • BCAR3 – Breast cancer anti-estrogen resistance protein 3
  • GRAP – GRB2-related adaptor protein
  • GRAP2 – GRB2-related adaptor protein 2
  • LDLRAP1 – low density lipoprotein receptor adaptor protein 1
  • NCK1 – NCK adaptor protein 1
  • NCK2 – NCK adaptor protein 2
  • NOS1AP – nitric oxide synthase 1 (neuronal) adaptor protein
  • PIK3AP1 – phosphoinositide-3-kinase adaptor protein 1
  • SH2B1 – SH2B adaptor protein 1
  • SH2B2 – SH2B adaptor protein 2
  • SH2B3 – SH2B adaptor protein 3
  • SH2D3A -SH2 domain containing 3A
  • SH2D3C – SH2 domain containing 3C
  • SHB – Src homology 2 domain containing adaptor protein B
  • SLC4A1AP – solute carrier family 4 (anion exchanger), member 1, adaptor protein
  • GAB2 – GRB2-associated binding protein 2--wikipedia
Ignoring these "adapters" is a gross mistake
look at this one for example"

NSP1 Defines a Novel Family of Adaptor Proteins Linking Integrin and Tyrosine Kinase Receptors to the c-Jun N-terminal Kinase/Stress-activated Protein Kinase Signaling Pathway*

  1. Timothy A. Stewart
Basically this one tells you, without me c-JUN will not be stimulated and Neoplastic processes induced by prolonged c-JUN stimulation will not occur!
" In contrast, cell contact with fibronectin results in Cas phosphorylation and a transient dissociation of NSP1 from p130Cas. Increased expression of NSP1 in 293 cells induces activation of JNK1, but not of ERK2. Consistent with this observation, NSP1 increases the activity of an AP-1-containing promoter. Thus, we have described a novel family of adaptor proteins, one of which may be involved in the process by which receptor tyrosine kinase and integrin receptors control the c-Jun N-terminal kinase/stress-activated protein kinase pathway." an interesting observation, conclusion by the authors...

OF INTEREST ALSO IS THE BCAR3 IS PROPOSED IN THE RESISTANCE OF BREAST CANCERS TO TAMOXIFEN, IS IT A FACTOR OR MECHANISM OF DESENSITIZATION?

SUFFICE IS TO SAY THAT OUR EVOLVING UNDERSTANDING OF THESE ADAPTERS SHOULD BE OFTEN REVISITED. BECAUSE THEY ARE INDEED "WILD GENES"...

(ARE THEY THE REASONS FOR ALOPECIA OR SKIN/DERMATITIS  SIDE EFFECTS OF THERAPEUTIC DRUGS?-NAUGHTY OBSERVATION TO TEASE RESEARCHERS AROUND THE WORLD!)

Friday, August 30, 2013

STUNTED HEART

If only death at old age is acceptable as it seems in people interviewed, then geneticist need to spell out phenomena occurring during "stunted heart"...is it the Notch, or is it stoppage of ion channel flow...to be continued!

Untapped new interventions in Traget therapy.

There are phenomena that only nature knows to do well such as
1.Aging of a cell
2.Apoptosis, a controlled programmed death
3.keeping a cell alive or active without a nucleus (Red cell)
4.deleting a gene in a living cell to fully commit it to a function ( T cell Vs B cell differentiation)
5.The differentiation itself...
and many more function.
The funny thing is we are always behind trying to catch-up.
We know from experience that a rotten fruit need to be removed from a bunch because the one in contact with them will also go "awry" as if talked to by the rotten one!  Is it the NOTCH or is-it just timing intervention of MTOR for aging?
There is deep in a cell a language or a voice that tell it to do something because it it is time, and we know this is a chemical message.  Scientist are trying to learn this language still today...Can we ask a Melanoma cell to remove its nucleus like the red cell does, can we master this process, can we ask a Sarcoma cell to delete a gene that prove to be driving the neoplastic process. Is ubiquitylation effective in this process.  So far globally, our targeting therapy is focused at one level (one or multiple kinase attack on the same pathways) and combining therapies is a way of hitting even higher number of pathways.  But today these combinations some time work opposite to one another, mitigating our results or simply not being additive in terms of result achieved.  We need an "integrated staged " attack, and here we need computer models...

Thursday, August 29, 2013

NEED FOR BIOMARKERS

"Cardiovascular Autonomic Dysfunction Predicts Outcomes in Diabetes

Marlene Busko

OULU, FINLAND AND GYEONGGI-DO, SOUTH KOREA — Among patients with stable CAD and type 2 diabetes, measures of autonomic function--such as heart-rate recovery after exercise--may help predict the risk of short-term adverse cardiovascular events, a new study hints[1]. A second study reports that autonomic dysfunction is strongly linked with a greater risk of severe hypoglycemia in patients with type 2 diabetes[2]".(MEDSCAPE) GO TO ARTICLE FOR FULL INFORMATION.

========================================================

This article examplify what we are talking about
autonomic dysfunction is home to the Wnt, Notch,ion channel,  and related membrane
ions channel, NEDD4, and all the FAKs.  Best we can come with is Heart rate reovery after exercise for autonomic dysfunction monitoring...
Medical revolution is needed!!!!

Wikipedia
"E3 ubiquitin-protein ligase NEDD4 also known as neural precursor cell expressed developmentally down-regulated protein 4 (NEDD-4) is an enzyme that in humans is encoded by the NEDD4 gene.[1][2] NEDD4 has been shown to ubiquitinate and therefore down regulate the epithelial sodium channel in the collecting ducts of the kidneys, therefore opposing the actions of aldosterone and increasing salt excretion. In Liddle's Syndrome NEDD4 is unable to bind to the ENaC and uncontrolled natriuresis occurs."

Tuesday, August 27, 2013

Clinical questions in Essential Hypertension (Gene basis)

Status of the RET gene in Hypertension induced stroke
Let's be frank about this our current understanding of Hypertension and its various therapeutic intervention is not adequate. Strokes appear to occur in a rampant way and the current treatments  are clearly insufficient.The epidemic of Obesity is complicating our progress even more.  Yes obesity is a clear threat to Hypertension control as fat tissue is known to produce ingredients that worsen our autonomic control of blood pressure (we know for example that Sortilin is expressed in testis muscles and fat).
The point is that we can't predict when the autonomic system protecting the brain may deem that enough elevation of blood pressure is too much to "close" the blood vessel long enough to cause an Ischemic stroke!  We suspect that the up and down of Blood pressures cause damages to blood vessels, possibly contributing to a subsequent weakening of the vessel structure prior to some of the bleeding strokes.  But we have no way of predicting these events or estimating the damages early enough to predict a stroke.  (Are there better Biomarkers out there?
One speculation comes to mind, most of the growth factors of the autonomic system have a cystein block, can deacetylation be an effective prevention?  can we measure these compound as Biomarkers  ? can Interferon be used in the prevention of stroke?
You heard me before about the Wnt and the Notch!
But I am not kidding this is where it is all playing out!
There is a tone to blood vessel that is under autonomic control, not our will...And the closest gene controlling these nerve that we know of is VEGF and RET.  Frankly let's look closely at this RET gene now since we have inhibitors (ie Vandetanib).  One of the side effect of Avastin is high blood pressure, did any one care to measure if those with high blood pressure have elevated or amplification of RET?  This RET is a member of the cadherin family (and the Wnt is not to far as you can see!)...what we need to do is to take a group of willing people with hypertension and test them for level of proteins from the GDNF family, and find new biomarkers! (Neurotensin included of course)
Let's go to work people!

(RET gene is a potential tumor inducer because it interacts with a "wild gene" Grb2)

IT'S IN THE NEWS!

JAKAFI (RUXOLITINIB)IMPROVED SURVIVAL WHEN GIVEN WITH XELODA IN RECURRENT AND REFRACTORY METASTATIC PANCREATIC CANCER,OPENING NEW DOORS TO NEW CLINICAL TRIALS IN THIS DISEASE!

JAKAFIRuxolitinib Improves Survival When Given with Capecitabine in Recurrent or Refractory Pancreatic Cancer


Published Online: Friday, August 23, 2013
Jakafi

The survival rate of patients with recurrent or treatment-refractory pancreatic cancer was improved when patients were treated with a combination of ruxolitinib (Jakafi) and the chemotherapy agent capecitabine compared to patients who were treated with capecitabine alone, according to results of a phase II proof-of-concept study.

The drug’s manufacturer, Incyte, announced the results on Wednesday. Full results from the study are expected to be presented at a future scientific meeting.

Ruxolitinib is a potent and selective oral JAK1 and JAK2 inhibitor that was approved by the FDA in 2011 for the treatment of myelofibrosis, a form of blood cancer characterized by bone marrow failure and spleen enlargement.
- See more at: http://www.targetedhc.com/articles/Ruxolitinib-Improves-Survival-When-Given-with-Capecitabine-in-Recurrent-or-Refractory-Pancreatic-Cancer#sthash.P1CrDDpt.dpuf

Ruxolitinib Improves Survival When Given with Capecitabine in Recurrent or Refractory Pancreatic Cancer


Published Online: Friday, August 23, 2013
Jakafi

The survival rate of patients with recurrent or treatment-refractory pancreatic cancer was improved when patients were treated with a combination of ruxolitinib (Jakafi) and the chemotherapy agent capecitabine compared to patients who were treated with capecitabine alone, according to results of a phase II proof-of-concept study.

The drug’s manufacturer, Incyte, announced the results on Wednesday. Full results from the study are expected to be presented at a future scientific meeting.

Ruxolitinib is a potent and selective oral JAK1 and JAK2 inhibitor that was approved by the FDA in 2011 for the treatment of myelofibrosis, a form of blood cancer characterized by bone marrow failure and spleen enlargement.
- See more at: http://www.targetedhc.com/articles/Ruxolitinib-Improves-Survival-When-Given-with-Capecitabine-in-Recurrent-or-Refractory-Pancreatic-Cancer#sthash.P1CrDDpt.dpuf

Ruxolitinib Improves Survival When Given with Capecitabine in Recurrent or Refractory Pancreatic Cancer


Published Online: Friday, August 23, 2013
Jakafi

The survival rate of patients with recurrent or treatment-refractory pancreatic cancer was improved when patients were treated with a combination of ruxolitinib (Jakafi) and the chemotherapy agent capecitabine compared to patients who were treated with capecitabine alone, according to results of a phase II proof-of-concept study.

The drug’s manufacturer, Incyte, announced the results on Wednesday. Full results from the study are expected to be presented at a future scientific meeting.

Ruxolitinib is a potent and selective oral JAK1 and JAK2 inhibitor that was approved by the FDA in 2011 for the treatment of myelofibrosis, a form of blood cancer characterized by bone marrow failure and spleen enlargement.
- See more at: http://www.targetedhc.com/articles/Ruxolitinib-Improves-Survival-When-Given-with-Capecitabine-in-Recurrent-or-Refractory-Pancreatic-Cancer#sthash.6YZwYBXR.dpuf

Ruxolitinib Improves Survival When Given with Capecitabine in Recurrent or Refractory Pancreatic Cancer


Published Online: Friday, August 23, 2013
Jakafi

The survival rate of patients with recurrent or treatment-refractory pancreatic cancer was improved when patients were treated with a combination of ruxolitinib (Jakafi) and the chemotherapy agent capecitabine compared to patients who were treated with capecitabine alone, according to results of a phase II proof-of-concept study.

The drug’s manufacturer, Incyte, announced the results on Wednesday. Full results from the study are expected to be presented at a future scientific meeting.

Ruxolitinib is a potent and selective oral JAK1 and JAK2 inhibitor that was approved by the FDA in 2011 for the treatment of myelofibrosis, a form of blood cancer characterized by bone marrow failure and spleen enlargement.
- See more at: http://www.targetedhc.com/articles/Ruxolitinib-Improves-Survival-When-Given-with-Capecitabine-in-Recurrent-or-Refractory-Pancreatic-Cancer#sthash.6YZwYBXR.dpuf

Monday, August 26, 2013

estrogen receptor, another wild gene


 Estrogen receptor is another  "wild gene"
 (Interacts with so many other genes to hide its full effect, wild genes will eventually hit another gene or a silent mutation, enough to lead to a neoplastic process).

WIKIPIDIA TELLS

"Genomic

In the absence of hormone, estrogen receptors are largely located in the cytosol. Hormone binding to the receptor triggers a number of events starting with migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequent binding of the receptor dimer to specific sequences of DNA known as hormone response elements. The DNA/receptor complex then recruits other proteins that are responsible for the transcription of downstream DNA into mRNA and finally protein that results in a change in cell function. Estrogen receptors also occur within the cell nucleus, and both estrogen receptor subtypes have a DNA-binding domain and can function as transcription factors to regulate the production of proteins.
The receptor also interacts with activator protein 1 and Sp-1 to promote transcription, via several coactivators such as PELP-1.[2]
Direct acetylation of the estrogen receptor alpha at the lysine residues in hinge region by p300 regulates transactivation and hormone sensitivity.[19]"
"
AT CRBCM, WE WOU;D LIKE TO STRESS THAT ONE OF THE MOST SIGNIFICANT EFFECT OF ESTROGEN IS ITS INDUCTION OF PROFOUND INDUCTION OF EPIGENETIC CHANGES BY A COMPLETE MAKE OVER OF PATTERNS OF METHYLATION, AND ITS CO-PARTNER, THE PATTERN OF miRNA(s), AS IF THIS HORMONE ATTACHES TO mRNA OR TO POLYMERASES.  ONE OF THE MOST AFFECTED GROUP OF GENE THE CLASS I ANTIGENS HLA-A AND B.  THIS SINGLE FACT (ESTROGEN SURGE AND SUBSEQUENT CHANGE IN METHYLATION PATTERNS  ) CONTROLS THE WORSENING OF MOST AUTOIMMUNE DISEASES IN WOMEN ENTERING AGE OF FERTILITY (LUPUS IS BAD BETWEEN 15-45 YEARS OF AGE IN WOMEN) . IT IS ALSO THE CAUSE OF ENDOMETRIAL CANCER IN UNOPPOSED ESTROGENIC EXPOSURE, AND ACTUALLY KILLS WOMEN BY MYOCARDIAL SILENT ATTACK AT MENOPAUSE!


ESTROGEN GENE :  "
Binds DNA as a homodimer. Can form a heterodimer with ESR2. Isoform 3 can probably homodimerize or heterodimerize with isoform 1 and ESR2. Interacts with FOXC2, MAP1S, SLC30A9, UBE1C and NCOA3 coactivator By similarity. Interacts with EP300; the interaction is estrogen-dependent and enhanced by CITED1. Interacts with CITED1; the interaction is estrogen-dependent. Interacts with NCOA5 and NCOA6 coactivators. Interacts with NCOA7; the interaction is a ligand-inducible. Interacts with PHB2, PELP1 and UBE1C. Interacts with AKAP13. Interacts with CUEDC2. Interacts with KDM5A. Interacts with SMARD1. Interacts with HEXIM1. Interacts with PBXIP1. Interaction with MUC1 is stimulated by 7 beta-estradiol (E2) and enhances ERS1-mediated transcription. Interacts with DNTTIP2, FAM120B and UIMC1. Interacts with isoform 4 of TXNRD1. Interacts with KMT2D/MLL2. Interacts with ATAD2 and this interaction is enhanced by estradiol. Interacts with KIF18A and LDB1. Interacts with RLIM (via C-terminus). Interacts with MACROD1. Interacts with SH2D4A and PLCG. Interaction with SH2D4A blocks binding to PLCG and inhibits estrogen-induced cell proliferation. Interacts with DYNLL1. Interacts with CCDC62 in the presence of estradiol/E2; this interaction seems to enhance the transcription of target genes. Interacts with NR2C1; the interaction prevents homodimerization of ESR1 and suppresses its transcriptional activity and cell growth. Interacts with DYX1C1. Interacts with PRMT2. Interacts with PI3KR1 or PI3KR2, SRC and PTK2/FAK1. Interacts with RBFOX2. Interacts with STK3/MST2 only in the presence of SAV1 and vice-versa. Binds to CSNK1D. Interacts with NCOA2; NCOA2 can interact with ESE1 AF-1 and AF-2 domains simultaneously and mediate their transcriptional synergy. Interacts with DDX5. Interacts with NCOA1; the interaction seems to require a self-association of N-terminal and C-terminal regions. Interacts with ZNF366, DDX17, NFKB1, RELA, SP1 and SP3. Interacts with NRIP1 By similarity. "( UniProtKB/Swiss-Prot)

=======================A CAREFUL REVIEW OF EACH CITED GENE IS WARRANTED TO UNDERSTAND THE FULL SCOPE OF ESTROGEN INFLUENCE===============

The future of medicine

The life span of a man or woman would be 10-20 years longer should modern medicine was efficient at monitoring human health, detecting deviations to future standards biomarkers and driver genes of diseases timely, and treating using targeted approaches efficiently delivered.  It is also true that given the number of processes to be monitored, we have to wake up to the fact that future doctors would be a computer since minutia sorting through the multitude of genes and their state and prominent interactions would be hard to process by one human brain!  The quicker we realize this, the better for human kind!   The understanding of current top physicians is minuscule compared to the task at hand!  We are at the door of the cell which is cracked barely to see what is inside, and our understanding is quite preliminary because at a "gross level" not at the NANO-PARTICULE LEVEL.  Indeed, if we are planning to deliver medicine using nano-vehicles, we got to get to this level of science!
The surprising part to this is that things are in our side!  Life wants to survive, and any help it can get will be for the better.  And we have not sufficiently help because we still do not know enough and mismanage our resources.  The current knowledge is preliminary and fragmented at best!.
We know life wants to survive because when it starts it moves deliberately to produce an organism that is able to sustain life by properly processing the environment. A viable unit such as man,
full of purpose even beyond its corporal limits.  This drive to conquer the environment come deep from the purpose of life: survival and differentiate and adapt if necessary!  Every important lesson learned is written into our genes for a very quick answer to stimuli that challenges us daily.  The writing is in the epigenic area of our cells.  Indeed methylation of genes is not random.  The writing is is in the Macromolecules organized in "Core Binding proteins", into pattern of methylation of genes through CPGs but also through miRNA which regulate gene expression!
The drive to life preservation and survival follow strict forces of nature occurring into chemical chain reactions following basic chemical rules (laws of nature).  These forces are deliberate, organized and constantly occuring driven again by patterns learned.  The unlearned stimulations go through the NF-kB which reads the epigenic repertoire that exist, and ready to write new ones! 

Defining new new Biomarkers is an important step.
And we have started to do just that.  Today the diagnosis POEMS (polyneuropathy, Organomegaly,Endocrinopathy, M proteins, and SKIN changes ) include one criteria that was unheard of 20 years ago, "elevation of VEGF (Vascular Endothelial Growth Factor)". (to be continued)

Sunday, August 25, 2013

INTEGRATING THE CAUSAL FACTORS OF GI MALIGNANCIES/QUESTIONS IN GI MALIGNANCIES

Indolency: one of the biggest unresolved question in cancer genetics is the clear determination of
what genes are determinant for indolency:  genes'role is defined by their position in a critical pathway and by the number of interactions they have.  It appears that a genes with multiple interactions (wild gene  i.e Grb2,Androgen gene,FYN) could definitely impact considerably cellular events and could indeed force things into the neoplastic way or direction.  There are gene that are critical as the are located upstream on an important gene.  Our own experience has stressed the importance of gene which induce malformation if lacking (i.e MITF)

MITF microphthalmia-associated transcription factor [ Homo sapiens (human) ]

Part of the "Indolent tumor gene" are those found in both preneoplastic and malignant diseases.  Although caution should be brought here since an early occuring Mutation could be just a normal irreversible process to full neoplasia.   Other than preneoplastic, there are Cancers that are truly indolent (with survival in years). The Neuroendocrine tumors are cited repeatedly (GIST also).  These are clearly identified as those cancers with a limited numbers of Driver Mutations or with gene abnormality responsive to some well known Target therapy or chemosensitivity!   Our experience is pointing to evidence that Regulator genes are generally bad actors!
TO BE CONTINUED==============================
====================
Hepatocarcinoma Vs Pancreatic Vs Neuroendocrnie cancers
Familial cancers different from random cancers (Genetically)
Known abormal CBF
what are the known targets
what are the known biomarkers

Ingestion of Irritant
Body mass: Insulin,lipolysis, Fat Acid, High TNF, metalloproteases,calories,salt,nitrates,iron in drinking water,type A
Genetic (racial factors)
location and culture (Anti-Oxidant, FE, Zinc, Magnesium,)

GERD influence Chronic irritation
meaning NF-KB C-JUN TGF, CYCLINS
Increased Gastric secretion? Glandular secretion MUC1
HLA
MEK-and Wnt, Notch- Metaplasia
Androgen, MTOR (Silencing, and TNF), smoking, ARYL Hydrocarbon

Medication may induce Atrophic and mitigateNeoplastic transformation

Saturday, August 24, 2013

FAK INHIBITORS ARE HERE AS A MATTER OF FACT!

Verastem Enters Biomarker Agreement with LabCorp for Cancer Stem Cell Agent Companion Diagnostic




:The identification of patients most likely to benefit from targeted therapy is critical to accelerating the drug development and approval process,” said Henri Termeer, Verastem Lead Director.
Clinical assay validation is an integral component to all companion diagnostics entering an FDA approval process.
Pioneering research by Robert Weinberg, Ph.D., Verastem cofounder and chair of the Scientific Advisory Board, and others have demonstrated that FAK signaling plays a central role in the tumor-initiating capability of cancer stem cells and ultimate disease progression. VS-6063 is designed to target and kill cancer stem cells by inhibiting FAK signaling.
Mesothelioma tumors lacking the tumor suppressor Merlin appear to be particularly sensitive to FAK inhibitors. As shown recently at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, sensitivity due to lack of Merlin is evident in both research models and early clinical proof-of-concept.
“We believe the approximately 50% of mesothelioma patients lacking Merlin may be particularly responsive to treatment with FAK inhibitors,” said Dan Paterson, Verastem Vice President, Head of Corporate Development and Diagnostics. “LabCorp is the perfect partner to progress our research on Merlin into a companion diagnostic for VS-6063.”"
=======================================================================
 SANTA CRUZ BIOTECHNOLOGY
FAK Inhibitor 14 is a selective FAK (focal adhesion kinase) inhibitor that displays no significant activity for a range of other kinases including PDGFR, EGFR, and IGF-RI. FAK Inhibitor 14 has been shown to prevent FAK autophosphorylation at the putative activation site, tyrosine 397 (IC50 of 1μM). FAK Inhibitor 14 has been shown to promote cell detachment and inhibit cell adhesion in vitro, and to exhibit antiproliferative activity in a variety of human tumor cell lines in vivo such as: breast cancer cell lines BT474 and MCF-7, pancreatic cancer cell lines Panc-1 and Miapaca-2, and neuroblastoma cell lines MYCN+/MYCN- (with a greater effect on the negative isogenic form). FAK Inhibitor 14 has also been used to study the conformation and self replication methodology of bis capped porphyrins.
Technical Information
Appearance:Gray solid
Physical State:Solid
Solubility:Soluble to 100 mM in Water and to 75 mM in DMSO
Melting Point:>300 °C lit.
Safety and Reference Information
PubChem CID:78260
MDL Number:MFCD00012970
EC Number:224-822-6
SMILES:C1=C(C(=CC(=C1N)N)N)N.Cl.Cl.Cl.Cl
For Research Use Only. Not Intended for Diagnostic or Therapeutic Use.
References
1. Thordarson, P., et al. 2003. Org. Biomol. Chem. 1: 1216-1225. PMID: 12926398
2. Golubovskaya, V.M., et al. 2008. J. Med. Chem. 51: 7405-7416. PMID: 18989950
3. Hochwald, S.N., et al. 2009. Cell Cycle. 8: 2435-2443. PMID: 19571674
4. Beierle, E.A., et al. 2010. Cell Cycle. 9: 1005-1015. PMID: 20160475

FAK Inhibitor 14 (CAS 4506-66-5) Product Citations
See how others have used FAK Inhibitor 14 (CAS 4506-66-5).


3 total citations
Bartolomé RA. et al. 2013. Cadherin-17 interacts with α2β1 integrin to regulate cell proliferation and adhesion in colorectal cancer cells causing liver metastasis. Oncogene. : . View PubMed Entry
Marley, K. et al. 2012. Phosphotyrosine enrichment identifies focal adhesion kinase and other tyrosine kinases for targeting in canine hemangiosarcoma. Vet Comp Oncol. 10: 214-222. View PubMed Entry
Park, JA. et al. 2010. The chitinase-like protein YKL-40 is secreted by airway epithelial cells at baseline and in response to compressive mechanical stress. J Biol Chem. : -. View PubMed Entry
SDS
Related Product Categories
 GIVEN THE NON SPECIFICITY OF THESE BIOMAKERS, I SUSPECT THESE INHIBITORS WILL HAVE A ROLE IN MAINTENANCE AND PREVENTION SETTING UNLESS IT IS ASSUMED THERE IS A DRIVER MUTATION HIDDEN IN THIS PATHWAY!

FAK COULD THEREFORE BE PROPOSED (ALONG WITH METALLOPROTEASE) AS A BIOMARKER IN CANCERS!

WHEN A PROTEIN, A RECEPTOR, ADAMS, OR EVEN AN ANCHOR IS "DETACHED" FROM CELLULAR MEMBRANE, AN FREE EDGE REMAINS AT THE MEMBRANE AND COULD POTENTIALLY ENGAGE A SLEW OF MOLECULES.  WE HAVE TERMED THIS POTENTIAL A "CHELOID EFFECT" WHEN REPAIR GOES WRONG!  THE Wnt AND THE NOTCH BEING PHENOMENA AT THE MEMBRANE, WILL BE CLEARLY ENGAGED, AND THE Src, AND DOWN STREAM PATHWAYS COULD POTENTIALLY BE ENGAGED (THEY ARE OBVIOUSLY WHEN A RECEPTOR IS DETACHED).
THE AMOUNT OF MEMBRANE FREE EDGES DEPEND ON CELLULAR INTERACTIONS WITH STIMULI INDEPENDENT OF ITS NATURE.  THE MOLECULAR NATURE OF THIS FREE EDGE OBVIOUSLY WILL INTERACT WITH BYSTANDER AND NEIGHBORING MOLECULES.  THEREFORE A CELL UNDER CONSTANT STIMULATION BY IRRITANT IS A "SUSCEPTIBLE" TO POTENTIAL NEOPLASTIC TRANSFORMATION.  THE NUMBER OF FREE EDGES APPEAR TO HAVE TO CORRELATE WITH CELLULAR EXPOSURE, AND COULD THEREFORE BE AN IMPORTANT BIOMARKER OF CELLS INVOLVED WITH NEOPLASIA.  THIS OF COURSE WILL BE NON SPECIFIC, BUT ASSOCIATED WITH OTHER BIOMARKERS, COULD BE CLINICALLY USEFUL!

PROOF IS HERE!

Biomarkers: FAK autophosphorylation independently predicts recurrence of gastric cancer

Shreeya Nanda!

Clinical importance of the cheloid factor

"Cheloid Factor"

Cellular repair may contribute to the recognized increased risk of cancer in areas that have been traumatized.  For example when Radiation was received or a simple surgery was performed.
Intuitively, we assume that stimulation of tissue repair mechanisms and the inflammatory response leads to the increased risk, but to this date there has not sufficient data been collected for indepth checking, and the FAK (focal adhesion Kinases).  Certainly, if the inflammatory and related NF-kB (MAPK), C-jun were the only drivers of the risk of cancer in surgery sites, we believe this risk would be much more prominent that it is, given the frequency of surgical interventions?

Another evidence that the cheloid factor is needed in the cancerization risk is the fact that " a large chinese study showed no benefit in the prevention of gastric cancer with eradication of H.Pylori" (Grothey ).  Meaning that the mere decrease of an Infectious impetus which modulates the NF-kB and the level of cyclins, failed to globally affect the risk of cancer development.  But we know that this Infection needs to be eradicated in patients with demonstrasted gastric Ulcer  disease (Grothey).  Here, we use the presence of an ulcer as a putative presence of disturbance at the FAK! We need funding for such a demonstration!

Conceivably, FAK which involves the Wnt and Notch and their associated involvement of cell polarity (as discussed earlier in depth and breadth) could also play a significant role in the risk for hepatoma. Indeed, the mere presence of Hepatitis B or C does not lead to Hepatoma. It is the evidence of disturbance at regeneration and repair which involves the FAK that leads to Hepatoma.  In fact, in the Western World, Hepatoma is more generated by alcoholic and non alcoholic "trauma" followed by uncontrolled Repair.  The focal adhesion molecules are a significant part of these repair events at the cellular level.  The point is, that with every protein leaving the membrane, with every stimulated receptor detaching from the membrane, with every ions channel stimulated and some tension in these channels, there is potentially an activity going on at the FAK!  and making these events very frequent at the membrane!  Any chronic exposure increases these FAK events further.  The coexistence of any other failure (Mutations at P53, BRCA, p15 or 16, DPC, Rb1 or just at the Glycans ie Heparan sulfate- covering detaching receptors, and at the "switch" molecules (SOS, and others phosphorylation regulators -APC GENE) will exacerbate the risk of neoplastic development.  The interaction with a wild gene will completely establish the neoplastic transformation..

The Melanoma example is just another example of the "cheloid factor" history as solar trauma exposes us to large amounts of FAK solicitations.  Radiation trauma to the marrow adds JAK2 to the danger of FAK sollicitations or influence (proof of concept needed) opening the door to cellular malignancies from the marrow.  Of course, the resulting fibrosis will be Cyclins and Tumor growth factors (TNF) related detaching more receptors and exposing FAK or Focal Adhesions membrane molecules!

Under this prism, Neoplasia seems to be linked not only to specific genes that must Mutate, but more to the global number of Focal adhesion Molecules exposed.   The fact that anti-inflammatory agents which decrease the number of detaching receptors induced by inflammatory cytokines, reducing FAK exposure and globally reducing Neoplastic risk, adds more credence to this theory! (Proof of concept)   Antioxidant by reducing free radicals and resulting sollicitation of proteins attached to the membranes, will do just the same!  Indeed, the very notion of Biomarkers followed in the serum,  marks protein rates and FAK exposure!

(IF ANYTHING, THIS THEORY MUST BE PURSUED ! AND CPRIT CAN HELP!)

Friday, August 23, 2013

BRUSHING FURTHER!

Dear Mutombo,
Thank you for attending Genetics and Genomics BioConference Live!

We have great news! The event was so successful that it will now be available on-demand until January 2, 2014.

Feel free to log in to attend the webcasts, visit exhibitor booths, and exchange messages with experts and sponsors.
Earn CME, CE, and CEU Credits.  Learn more by clicking here.


Thank you for your participation! We look forward to seeing you at the next event!
- the BioConference Live team

Need technical support?
Email support@bioconferencelive.com
Phone: +1-714-463-4673
See our
Frequently Asked Questions 

Questions in Hodgkin Disease

QUESTIONS IN HODGKIN DISEASE

1.WHY A BIMODAL INCIDENCE BY AGE ?
2.WHY HX OF MONONUCLEOSIS INCREASES 3X THE RISK OF HODGKIN DISEASE ?
3.THE INFECTIOUS PROCESS MUST LEAVE A DEFICIENCY FOR HODGKIN LYMPHOMA TO DEVELOP (HIV, EBV,  BONE MARROW TRANSPLANT) ?CD8, HLA DR (ACQUIRED IMMUNITY) ?
4.DOES EXTRANODAL INFILTRATION MEAN T-CELL INVOLVEMENT OR JUST FAILURE OF A BLOOD VESSEL ?
(to be continued)

THE "CHELOID FACTOR" AT THE CELLULAR MEMBRANE!

We tend to be excited about intracellular pathways as they travel through the Cytosol and affect epigenetic and nuclear phenomena. And our excitement has been justified since we have been able to affect cellular life by targeting various pathway molecules.  But one should stress a particular event occurring at the membrane that mimics "wound phenomena".  Aside for providing a physical boundary of the cell, the membrane is one of the most important "organs" of the cell.  It is in itself a very chemically vibrant living "cellular tissue ".  When you start reading about the cell they tell you about the layers of proteins and lipids that make up the cellular membranes.  But this picture is far from the truth, the membrane is like the wall of a brick house.  With each brick different from the next.  Some of these bricks are called Integrins (I guess because they are an integral part of the membrane).  Some of these bricks have a Cyclin, some have a growth factor!  In fact, the membrane here serves as a reserve of these molecules. Some bricks can be divided in 2 portions.  One portion that can "FLIP" inside when needed (This portion contains the cyclin, for example) and one portion that can "FLOP" outside (this portion contains a Metalloprotease).  (see my post on FLIPPASE and FLOPPASE) The point is that once the brick is used there remains a hole with sharp edges.  These edges are called "FOCAL ADHESION Molecules" (KINASES) in a cell and are governed by the PTK2 gene!  (and of course PYK2)

PTK2:

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Protein tyrosine kinase 2

PDB rendering of the C-terminal FAT domain based on 1k04[1].
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PTK2; FADK; FAK; FAK1; FRNK; PPP1R71; p125FAK; pp125FAK
External IDs OMIM600758 MGI95481 HomoloGene7314 ChEMBL: 2695 GeneCards: PTK2 Gene
EC number 2.7.10.2
RNA expression pattern
PBB GE PTK2 207821 s at tn.png
PBB GE PTK2 208820 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5747 14083
Ensembl ENSG00000169398 ENSMUSG00000022607
UniProt Q05397 P34152
RefSeq (mRNA) NM_001199649 NM_001130409
RefSeq (protein) NP_001186578 NP_001123881
Location (UCSC) Chr 8:
141.67 – 142.01 Mb
Chr 15:
73.21 – 73.42 Mb

PubMed search [1] [2]
PTK2 protein tyrosine kinase 2 (PTK2), also known as Focal Adhesion Kinase (FAK), is a protein that, in humans, is encoded by the PTK2 gene.[2] PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to each other and their surroundings) and spreading processes (how cells move around).[3] It has been shown that when FAK was blocked, breast cancer cells became less metastastic due to decreased mobility.[4](Wikepedia
=============================================================================

AND THEY ARE PLENTY TALKED ABOUT! 
===============================================================  I.E....

"Integrin-dependent translocation of phosphoinositide 3-kinase to the cytoskeleton of thrombin-activated platelets involves specific interactions of p85 alpha with actin filaments and focal adhesion kinase(JCB)"

 

The point is that at the membrane healing should occur after the "integrin" has been plucked off, but failure to heal may trigger the "cheloid effect".  In the cell, this is where the Src gene is, the Wnt (catenins) and the Notch are here, Caspase 3 is present, and death Receptors,etc... (things can get complicated really fast with these guys around! unless of course phosphorylation or other taming mechanisms come to play!)

Focal Adhesion kinases (FAK)

". FAK is typically located at structures known as focal adhesions, these are multi-protein structures that link the extracellular matrix (ECM) to the cytoplasmic cytoskeleton. Additional components of focal adhesions include actin, filamin, vinculin, talin, paxillin, tensin[7] and RSU-1."  This is what Taxol and Taxotere find their might!  (components of microtubules)

remember tensin is same as PTEN

NIH

" PTEN1

Also known as
BZS; DEC; CWS1; GLM2; MHAM; TEP1; MMAC1; PTEN1; 10q23del
Summary
This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. [provided by RefSeq, Jul 2008]"

Thursday, August 22, 2013

Example of neoplastic phenomena at work.

One example  of constant  stimulation is an estrogenic supply which leads to type I endometrial cancers. It appears that constantly giving Estrogens unopposed by progestins  leads to the stimulation of many genes including Grb2, a" wild gene" that provokes amplification of critical genes that are controlling the epithelium of the Uterus (Catenins and Muc1) leading to the disturbance of cell polarity and adhesions, events that are preceding hypertrophic transformation.  MUC 1 amplification will shield the cell from immune detection.  How much Sp1, EP 300, and RELA play to further broaden NF-kB amplification in this process remains to be further defined.
RELA is another "wild gene" very much in control of epigenetic phenomena induced by amplification of the NF-kB.
"RELA has been shown to interact with:

Processes of cancerization

One of the most intriguing steps in the neoplastic transformation is determining the actual event that led to its occurrence. We all have the perception that because of what we ingest unfortunately on a continuous basis (medications or foods we like - man clings to habits) something will get either amplified or suppressed.  Certain amplifications can be deleterious or beneficial depending of where they occur or what gene is involved.  It is apparent that involvement of "wild genes" (those with multiple interactions with others, including genes involved in shaping the body) are more likely to lead to malignant transformation (ie. the Androgen gene, FYN,Grb2, MTIF, etc).  Secondly, knocking out break to proliferation (P53, Rb1, PTEN, and the many CDK) seems also to be a prelude to a neoplastic transformation.   Alteration in "switch" genes (SOS) and molecules intermediary to various cellular/membrane events can also trigger a persistent stimulation or suppression that could affect cellular processes enough to upset a balance.  Chronic hypoxia has emerged to be a potent neoplastic process inducer....(to be continued)

A few questions in triple negative breast cancer

1.Could amplification of PIAS modulate enough the STAT to impact progression of triple negative Breast cancer?
2.Could modifiers of Sumoylation impact the prognosis of triple negative breast cancer?
3.Status of the Zimp10 in triple negative breast cancer?
4. Amplifying ART-27 to stop cellular proliferation?
5.blocking RCHY1 could restore P53 function in patient with non Mutated P53?
6.can anti-cortactin and supervillin block metastatic propensity of triple negative breast cancers?
watch brain mets?

Wednesday, August 21, 2013

Science without Borders!

Readers from 10 different countries visited the CRBCM blog today!
Thank you, friends and like-minded research fellows around the World,
including the USA, France, China, the United Kingdom, India, Malaysia,
the Netherlands, the Philippines and Serbia.
Your feedback matters to us, thank you, again!

NEW BIOMARKERS ARE NEEDED - URGENTLY!

One of the dreaded complications of chemotherapy is Pulmonary fibrosis or interstitial pneumonitis which ultimately takes the patient's life when Complete Response may have been achieved.   It is a dramatic event in the life of our patients, many survive and many have a limited fibrosis that allows life to go on after high doses of steroids.  Some patients suffer consequences of exposure to high dose steroids.   Suffice is to say that so far the Advisory committee has not called for any standard monitoring of this abnormal side effect, opting instead for a Head in the sand and crossing finger policy.  Oncologists hide behind the statement that the "patient was warned this could happen".  Knowing what we know, it is time to be rational about this and go after this side effect, understand it and monitor it carefully as we treat our patients!
So far repeated  pulmonary function testing has been our recourse in patients who are taking Bleomycin.  Those on Mitomycin, rarely do we give them a second dose...But when is comes to Gemzar for example, warning the patient that interstitial Pneumonitis could result, is all we do.  It is unclear whether what happens in the lung with Bleomycin Vs Gemzar is the same phenomenon at various intensities.  All we know is that the 2 phenomena both result in a limitation of lung function as a result of fibrosis.  Studies have suggested that the early use of Growth factors to maintain the hematologic status of the patient may exacerbate or increase the frequency/occurrence of pulmonary fibrosis. In the treatment of Hodgkin disease, we try to avoid prompt use of growth factors to that end!
Fibrosis involves cyclins for sure, but no one has come forward to propose a clear Interleukin or other to be monitored as we treat our patients.  The call for new bio-markers is therefore appropriate and pertinent!  Something is happening in our patients at various levels, let's go and define it pronto instead of clinging to lingering politics of prayers, crossing the fingers and keeping our head in the sand !

LET IT BE KNOWN, NEW ANTI EGFR FOR LUNG CANCER

August 13, 2013

Lilly Announces Phase III Necitumumab Study Meets Primary Endpoint of Overall Survival

Study found improved overall survival in patients with stage IV squamous NSCLC


INDIANAPOLIS, Aug. 13, 2013 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced that SQUIRE, a recently completed Phase III study, met its primary endpoint, finding that patients with stage IV metastatic squamous non-small cell lung cancer (NSCLC) experienced increased overall survival (OS) when administered necitumumab (IMC-11F8) in combination with gemcitabine and cisplatin as a first-line treatment, as compared to chemotherapy alone.
The most common adverse events occurring more frequently in patients on the necitumumab arm were rash and hypomagnesemia. Serious, but less frequent, adverse events occurring more often on the necitumumab arm included thromboembolism.
"We are pleased with these data which represent a potential advance in treatment for patients with squamous non-small cell lung cancer, which is a difficult cancer to treat," said Richard Gaynor, M.D., vice president, product development and medical affairs for Lilly Oncology. "If approved, necitumumab could be the first biologic therapy indicated to treat patients with squamous lung cancer."
Lung cancer is the leading cause of cancer death in the US and most other countries.[1] Non-small cell lung cancer (NSCLC) is much more common than other types of lung cancer, and accounts for 85 percent of all lung cancer cases.[2] Patients with squamous cell carcinoma represent about 30% of all patients affected by NSCLC.1
Lilly plans to present results from this study at a scientific meeting in 2014, and currently anticipates submitting to regulatory authorities before the end of 2014.
About the Study
SQUIRE enrolled 1093 patients (age greater than or equal to 18 years, ECOG PS 0-2) with histologically- or cytologically-confirmed, stage IV squamous NSCLC, who had received no prior therapy for metastatic disease. Patients were randomized to receive first-line necitumumab plus chemotherapy consisting of gemcitabine and cisplatin in study Arm A, or gemcitabine-cisplatin chemotherapy alone in study Arm B. Patients underwent  radiographic assessment of disease status (computed tomography or magnetic resonance imaging) every six weeks (+/- 3 days), until radiographic documentation of progressive disease (PD). Chemotherapy continued for a maximum of six cycles in each arm (or until there was radiographic documentation of PD, toxicity requiring cessation, or withdrawal of consent); patients in Arm A continued to receive necitumumab (IMC-11F8) until there was radiographic documentation of PD, toxicity requiring cessation, or withdrawal of consent.
About Necitumumab
Necitumumab is a fully human IgG1 monoclonal antibody that is designed to block the ligand binding site of the human epidermal growth factor receptor (EGFR). Activation of EGFR has been correlated with malignant progression, induction of angiogenesis and inhibition of apoptosis or cell death.
About Lilly Oncology
For more than four decades, Lilly Oncology, a division of Eli Lilly and Company, has been dedicated to delivering innovative solutions that improve the care of people living with cancer.  Because no two cancer patients are alike, Lilly Oncology is committed to developing novel treatment approaches. To learn more about Lilly's commitment to cancer, please visit www.LillyOncology.com
About Eli Lilly and Company
Lilly, a leading innovation-driven corporation is developing a growing portfolio of pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers — through medicines and information — for some of the world's most urgent medical needs.  Additional information about Lilly is available at www.lilly.com.
P-LLY
This press release contains forward-looking statements about the potential of necitumumab as a treatment for patients with squamous non small cell lung cancer and reflects Lilly's current beliefs. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. There is no guarantee that future studies will be positive or that necitumumab will receive regulatory approvals or prove to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.
Important Safety Information for GEMZAR® (gemcitabine for injection)
Myelosuppression is usually the dose-limiting toxicity with GEMZAR therapy.
ContraindicationGEMZAR is contraindicated in patients with a known hypersensitivity to gemcitabine.
Warnings and PrecautionsPatients receiving therapy with GEMZAR should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents.
Infusions of GEMZAR longer than 60 minutes or dosing more frequently than weekly resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of GEMZAR is influenced by the length of the infusion.
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with GEMZAR as a single agent, and the risks are increased when GEMZAR is combined with other cytotoxic drugs. Patients should be monitored for myelosuppression during therapy including a complete blood count with differential prior to each dose.
Pulmonary toxicity, sometimes fatal, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of GEMZAR. Discontinue GEMZAR in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy.
Hemolytic Uremic Syndrome (HUS), including fatalities from renal failure or the requirement of dialysis, can occur in patients treated with GEMZAR. Always monitor renal function prior to initiation of GEMZAR therapy and periodically during treatment. Use GEMZAR with caution in patients with renal impairment. Permanently discontinue GEMZAR in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy.
Drug-induced liver injury, including liver failure and death, has been reported in patients receiving GEMZAR alone or in combination with other potentially hepatotoxic drugs. Administration of GEMZAR in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of hepatic insufficiency. Assess hepatic function prior to initiation of GEMZAR and periodically during treatment. Discontinue GEMZAR in patients that develop severe liver injury.
GEMZAR can cause fetal harm when administered to a pregnant woman. Advise women of potential risks to the fetus.
GEMZAR is not indicated for use in combination with radiation therapy. When GEMZAR was administered within 7 days of receiving radiation therapy or concurrent with radiation therapy, toxicity of radiation therapy was increased. In a clinical trial, life-threatening mucositis, especially esophagitis and pneumonitis, occurred. Excessive toxicity has not been observed when GEMZAR is administered more than 7 days before or after radiation (nonconcurrent). Radiation recall has been reported in patients who receive GEMZAR after prior radiation.
Capillary Leak Syndrome (CLS) with severe consequences has been reported in patients receiving GEMZAR as a single agent or in combination with other chemotherapeutic agents. Discontinue GEMZAR if CLS develops during therapy.
Use in Specific Populations
GEMZAR is Pregnancy Category D. GEMZAR can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, GEMZAR is expected to result in adverse reproductive effects. It is not known whether GEMZAR is excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and efficacy of GEMZAR in pediatric patients have not been established.
No clinical studies have been conducted with gemcitabine in patients with decreased renal or hepatic function.
GEMZAR clearance is affected by age as well as gender.
Dose Modifications and Administration Guidelines
GEMZAR is for intravenous use only. Immediately and permanently discontinue GEMZAR for any of the following: unexplained dyspnea or other evidence of severe pulmonary toxicity, severe hepatic toxicity, Hemolytic Uremic Syndrome, or Capillary Leak Syndrome. Consider immediate discontinuation or dose modifications for severe nonhematologic toxicity according to the Dosage and Administration guidelines in the full Prescribing Information.
Serum creatinine, potassium, calcium, and magnesium should be monitored during combination therapy with cisplatin. See the manufacturers' prescribing information for more information on any drug indicated in combination with GEMZAR.
Abbreviated Adverse Reactions (%-incidence) — Patients receiving single-agent GEMZAR across 5 trials
The most severe adverse reactions (grades 3/4) in all patients receiving single-agent GEMZAR across five clinical trials were anemia (8), neutropenia (25), thrombocytopenia (5), hepatic transaminitis (increased ALT, 10; increased AST, 8), increased alkaline phosphatase (9), hyperbilirubinemia (3), nausea and vomiting (14), fever (2), and dyspnea (3).
The most common adverse reactions (all grades) in the same patient population were anemia (68), neutropenia (63), thrombocytopenia (24), increased ALT (68), increased AST (67), increased alkaline phosphatase (55), hyperbilirubinemia (13), proteinuria (45), hematuria (35), increased BUN (16), increased creatinine (8), nausea and vomiting (69), fever (41), rash (30), dyspnea (23), diarrhea (19), hemorrhage (17), infection (16), alopecia (15), stomatitis (11), somnolence (11), and paresthesias (10).
Abbreviated Adverse Reactions (%-incidence) 1st-line advanced NSCLC
The most severe adverse reactions (grades 3/4, with incidence of 5% or greater) with GEMZAR plus cisplatin for the first-line treatment of patients with NSCLC in comparative trials of a 28-day regimen (GEMZAR plus cisplatin versus cisplatin alone) and a 21-day regimen (GEMZAR plus cisplatin versus etoposide plus cisplatin), respectively, were neutropenia (57 vs 4, 64 vs 76); thrombocytopenia (50 vs 4, 55 vs 13); lymphopenia 28d (43 vs 17); anemia (25 vs 7, 22 vs 15); nausea and vomiting 21d (39 vs 26); nausea 28d (27 vs 21); vomiting 28d (23 vs 19); alopecia 21d (13 vs 51); neuromotor 28d (12 vs 3); hypomagnesemia 28d (7 vs 2); creatinine elevation 28d (5 vs 3); and infection (5 vs 1, 4 vs 8).
The most common adverse reactions (all grades, with incidence of 20% or greater) of the 28-day regimen (GEMZAR plus cisplatin versus cisplatin alone) and the 21-day regimen (GEMZAR plus cisplatin versus etoposide plus cisplatin), respectively, were anemia (89 vs 67, 88 vs 77); neutropenia (79 vs 20, 88 vs 87); thrombocytopenia (85 vs 13, 81 vs 45); lymphopenia 28d (75 vs 51); RBC transfusion (39 vs 13, 29 vs 21); platelet transfusions (21 vs 1, 3 vs 8); increased transaminases 28d (22 vs 10); nausea 28d (93 vs 87); vomiting 28d (78 vs 71); nausea and vomiting 21d (96 vs 86); alopecia (53 vs 33, 77 vs 92); creatinine elevation (38 vs 31, 2 vs 2); paresthesias 21d (38 vs 16); neuromotor 28d (35 vs 15); hyperglycemia 28d (30 vs 23); hypomagnesemia 28d (30 vs 17); infection (18 vs 12, 28 vs 21); neurohearing 28d (25 vs 21); diarrhea (24 vs 13, 14 vs 13); proteinuria (23 vs 18, 12 vs 5); neurosensory 28d (23 vs 18); hematuria (15 vs 13, 22 vs 10); and stomatitis (14 vs 5, 20 vs 18).
Abbreviated Adverse Reactions (%-incidence) 1st-line metastatic breast cancer
The most severe adverse reactions (grades 3/4, with incidence of 5% or greater) with GEMZAR plus paclitaxel versus paclitaxel alone, respectively, for the treatment of patients with metastatic breast cancer were neutropenia (48 vs 11); anemia (7 vs 4); thrombocytopenia (6 vs 2); alopecia (18 vs 22); fatigue (7 vs 2); increased ALT (6 vs 1); and neuropathy-sensory (6 vs 3).
The most common adverse reactions (all grades, with incidence of 20% or greater) in the same patient population were anemia (69 vs 51); neutropenia (69 vs 31); thrombocytopenia (26 vs 7); leukopenia (21 vs 12); alopecia (90 vs 92); neuropathy-sensory (64 vs 58); nausea (50 vs 31); fatigue (40 vs 28); vomiting (29 vs 15); and diarrhea (20 vs 13).
Abbreviated Adverse Reactions (%-incidence) Advanced recurrent ovarian cancer
The most severe adverse reactions (grades 3/4, with incidence of 5% or greater) with GEMZAR plus carboplatin versus carboplatin alone, respectively, for the treatment of patients with advanced ovarian cancer were neutropenia (71 vs 12); thrombocytopenia (35 vs 11); anemia (28 vs 11); constipation (7 vs 3); nausea (6 vs 3); and vomiting (6 vs 3).
The most common adverse reactions (all grades, with incidence of 20% or greater) in the same patient population were neutropenia (90 vs 58); anemia (86 vs 75); thrombocytopenia (78 vs 57); RBC transfusion (38 vs 15); nausea (69 vs 61); alopecia (49 vs 17); vomiting (46 vs 36); constipation (42 vs 37); fatigue (40 vs 32); diarrhea (25 vs 14); and stomatitis/pharyngitis (22 vs 13).
For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the accompanying full Prescribing Information.
GC HCP ISI ALL 14MAY2013
1 "Squamous cell carcinoma-similarities and differences among anatomical sites" - Am. J Cancer Re 2011;1(3):276)
2 U.S. National Institutes of Health. National Cancer Institute: SEER Cancer Statistics Review, 1973-2006
Refer to: Keri McGrath Happe (317) 370-8394 mcgrath_happe_keri_s@lilly.com